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P540 Therapeutic drug monitoring in ustekinumab: which factors affect trough levels?

R. Theeuwen*1, N. Provoost1, M. Koning1, A. Van der Meulen - de Jong1, D. J. A. Moes2, J. Maljaars1

1LUMC, Gastroenterology-Hepatology, Leiden, The Netherlands, 2LUMC, Department of Clinical Pharmacy and Toxicology, LEIDEN, The Netherlands

Background

Ustekinimab (UST) is a fully human monoclonal antibody against the p40 subunit of interleukin-12 (IL-12 and interleukin-23 (IL23). Efficacy of biological drugs can be optimised by ensuring adequate exposure to these drugs, by using trough level- based therapeutic drug monitoring. The aim of our research was to identify (bio)markers that influence UST trough levels. Furthermore, we aimed to assess the relationship between exposure and response to UST.

Methods

An observational study was carried out. All adult patients with Crohn’s disease that received UST treatment between December 2016 and November 2018 were included. Patient were treated with an initial intravenous induction therapy, followed by subcutaneous maintenance therapy . Patients demographics were collected (concomitant medication use, biological uses in the past, disease localisation, body weight, body-mass index), as were disease activity measures (Harvey–Bradshaw Index (HBI); faecal calprotectine (FCP); C-reactive protein (CRP) and Albumin. UST dosage and interval, trough levels and antibodies were collected as treatment specific data. Nonlinear mixed-effect modelling was used to estimate pharmacokinetic parameters based on the collected UST trough concentrations as implemented in the NONMEM software package (version 7.3.0) using PsN toolkit 4.7.0 and Piraña version 2.9.7 as modelling environment. Plotting of the results was performed using statistical software package R (v3.4.4) and R studio Version. Parameters calculated were Distribution Volume (V; litres) and clearance (CL/L/Day).

Results

50 patients (34.6% male, mean age 43 years, mean disease duration 17 years) with Crohn’s disease were included. A total of 365 doses UST were administered, and a total of 196 trough levels were measured. A one compartment model with first-order elimination was identified. The typical value of CL 0.28 L/day, V was 6.94 L. The inter-individual variability was estimated 35.1% for CL and 35.2% for V. Among the evaluated covariates, body weight significantly affected CL. In addition, baseline albumin and a CRP level >10 were found to be significantly affect V. In the exposure response analysis a relationship between HBI , CRP ad FCP and ustekinumab levels was identified. Patient with higher Ustekinumab levels had a lower HBI score and lower CRP and FCP levels.

Conclusion

A population pharmacokinetic model for ustekinumab was developed. Bodyweight, baseline albumin and CRP had a significant influence on ustekinumab pharmacokinetics. Patient with higher ustekinumab levels had a lower HBI score, lower FCP and lower CRP. These results show a possible rationale for TDM of ustekinumab however further research is required to establish a clear therapeutic window.